EP0067615A1 - Alkylthioderivate von Azabicyclobenzamiden, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen - Google Patents

Alkylthioderivate von Azabicyclobenzamiden, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen Download PDF

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Publication number
EP0067615A1
EP0067615A1 EP82302829A EP82302829A EP0067615A1 EP 0067615 A1 EP0067615 A1 EP 0067615A1 EP 82302829 A EP82302829 A EP 82302829A EP 82302829 A EP82302829 A EP 82302829A EP 0067615 A1 EP0067615 A1 EP 0067615A1
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Prior art keywords
formula
compound
group
alkylthio
alkyl
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English (en)
French (fr)
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EP0067615B1 (de
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Michael Stewart Hadley
David James Hunter
Eric Alfred Watts
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Beecham Group PLC
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Beecham Group PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof

Definitions

  • This invention relates to novel compounds, to novel pharmaceutical compositions containing these and other compounds and to a process for the preparation of such compounds.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or N-oxide and/or solvate thereof: wherein:
  • the invention also provides aprocess for the preparation of a pharmaceutical composition
  • a pharmaceutical composition comprising the admixture of a compound of formula (I), or a pharmaceutically acceptable salt, and/or a solvate and/or an N-oxide thereof and a pharmaceutically acceptable carrier.
  • compositions are _suitably adapted for oral or parental administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administerable compositions are preferred.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, tabletting agents, lubricants, disintegrants, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in the vehicle and filter sterilizing before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • Parental suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • the invention further provides a method of treatment of disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I), or a_pharmaceutically acceptable salt thereof, and/or -an solvate and/or N-oxide thereof or a pharmaceutical composition, as hereinbefore defined..to the sufferer.
  • an amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal.
  • a unit dose will normally contain 0.1 to 20 mg for example 0.5 to 10 mg, of the compound of the invention.
  • Unit doses will normally be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day such that the total daily dose is normally in the range 0.01 to 10 mg/ kg per day.
  • the compounds of the present invention have the ability to potentiate the effect of conventional analgesics in migraine treatment when administered concurrently with the analgesic.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I) and an analgesic.
  • the compound of the formula (I) and the analgesic, such as aspirin or paracetamol, are present in the composition in amounts generally similar to their usual effective dose.
  • composition can be a combination product, for example a tablet or capsule containing both a compound of the invention and an analgesic for oral administration, or a twin pack comprising the two active ingredients made up for separate administration.
  • the invention accordingly provides a method of treatment of migraine comprising the administration of an effective amount of a compound of the formula (I) and an analgesic.
  • the invention also provides a compound of formula (I), for use in the treatment of emesis, disorders relating to impaired gastro-intestinal motility and of disorders of the central nervous system.
  • the invention also provides a pharmaceutically acceptable salt and/or solvate and/or N-oxide of a compound of formula (I).
  • the invention further provides a process for preparing a pharmaceutically acceptable salt and/or solvate and/or N-oxide of a compound of formula (I).
  • Salts, hydrates and N-oxides of the compounds of formula (I) may be formed conventionally.
  • the salts may be formed for example by reaction of the base compound of formula (I) with a pharmaceutically acceptable organic or inorganic acid.
  • N-oxides of the nitrogen atom of the bicyclic ring system are produced by reaction of a compound of formula (I) with an organic peracid, such as m-chloroperbenzoic acid in, for example, a chlorinated hydrocarbon solvent at below ambient temperature.
  • an organic peracid such as m-chloroperbenzoic acid in, for example, a chlorinated hydrocarbon solvent at below ambient temperature.
  • Quaternary ammonium salts may be prepared by reaction of a compound of the present invention with the appropriate alkyl, aryl, aralkyl chloride, bromide or iodide. This reaction may be carried out in a solvent, such as acetone methanol, ethanol, dimethylformamide at ambient or elevated temperature with or without pressure.
  • a solvent such as acetone methanol, ethanol, dimethylformamide
  • the compounds of the present invention are dopamine antagonists and may generally be used in the treatment of emesis. Depending on their balance between peripheral and central action on the nervous system, they may also be used in the treatment of disorders relating to impaired gastrointestinal motility, such as retarded gastric emptying, dyspepsia, flatulence, oesophagal reflux and peptic ulcer and/or in the treatment of disorders of the central nervous system, such as psychosis.
  • Those compounds of the present invention which are of particular interest for their beneficial effect on gastric motility are the quaternary ammonium salts of the compounds of formula (I).
  • the compounds of formula (I) are of particular interest for treatment of disorders of the central nervous system.
  • R 1 examples include methoxy, ethoxy and n- and iso-propoxy, methylthio, ethylthio, and n- and iso-propylthio.
  • R 1 is a methoxy group.
  • Suitable examples of the second of R 2 , R 3 and R 4 include methylthio, ethylthio, n- and iso-propylthio.
  • the second of R 2 , R 3 and R 4 is methylthio.
  • Suitable examples of the third of R 2 , R 3 and R 4 include the following groups: hydrogen, chlorine, bromine, amino, C 1-4 alkanoylamino such as formylamino, acetylamino, propionylamino, n- and iso-butyrylamino, aminosulphonyl, and amino and aminosulphonyl substituted by one or two methyl, ethyl, n- or iso-propyl groups; n and iso-propoxy, methylthio, ethylthio, n- and iso-propylthio and hydroxy.
  • Particularly suitable examples of the third of R 2 , R 3 and R 4 include hydrogen, amino, C l-4 alkanoylamino, methoxy and methylthio.
  • R 3 is in the 4-position relative to the bicycloalkyl (alkyl) acylamino side chain for greater activity in the resultant compound of the formula (I).
  • R 4 is in the 5-position relative to the same acylamino side chain.
  • the third of R 2 , R 3 and R4 is Cl-6 alkoxy, it is preferably R 21 and is methoxy.
  • R 3 groups when R 2 is hydrogen include 4-amino and 4-(acylated amino), especially 4-acetylamino as defined.
  • R 3 then is 4-amino or 4-acetylamino.
  • R 4 groups include 5-alkylthio such as 5-methylthio.
  • R 4 groups of interest include substituted 5-aminosulphonyl as defined and 5-C 1-6 alkylsulphonyl or -sulphinyl, such as 5-aminosulphonyl and 5-methyl sulphonyl.
  • R 1 and R 2 taken together are methylenedioxy or ethylenedioxy
  • R 1 and R 2 are preferably ethylenedioxy.
  • R 5 examples include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, preferably hydrogen or methyl, in particular hydrogen.
  • Suitable examples of R 6 when C l-7 alkyl include methyl, ethyl, n- and iso-propyl and n-, sec-, iso- and tert- butyl, n-pentyl, n-hexyl, n-heptyl and 3-methylbutyl, 4-methylpentyl and 5-methylhexyl.
  • C 1-4 alkyl are particularly useful.
  • Suitable examples of R 6 when C l-4 alkyl include methyl, ethyl, n- and iso-propyl and n-, sec-, iso- and tert-butyl, particularly methyl,n-propyl and sec-butyl.
  • C 5-7 alkyl are also of interest.
  • Suitable examples of R 6 when C 5-7 alkyl include n-pentyl, n-hexyl and n-heptyl, 3-methylbutyl, 4-methylpentyl and 5-methylhexyl.
  • R 6 is a group -(CH 2 ) s R 7 as defined
  • suitable examples of R 7 include C 5-8 cycloalkyl, preferably cyclohexyl. s is preferably 1.
  • t is preferably 1.
  • R 8 is C 2-5 alkenyl
  • suitable examples thereof include vinyl, prop-l-enyl, prop-2-enyl, 1-methylvinyl, but-l-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl, 1-methylprop-l-enyl and 1-methylprop-2-enyl, in their E and Z forms where stere- isomerism exists.
  • a preferred C 1-5 alkenyl R 8 radical is vinyl, so that R 6 is preferably allyl.
  • R 8 is optionally substituted phenyl as defined above
  • suitable examples of such optional phenyl substituents include methyl, ethyl, n- and iso-propyl, n, sec- and tert- butyl; methoxy, ethoxy, n- and iso-propoxy; CF 3 , fluoro, chloro or bromo.
  • R 8 when optionally substituted phenyl is unsubstituted or 4-substituted by fluoro, chloro or methyl.
  • R 8 is thienyl it may be 2- or 3-thienyl, generally 2-thienyl.
  • p and q are suitably 0 to 1, preferably 1.
  • the amide and side chain nitrogen atoms are separated by a minimum of 2 or 3 carbon atoms, preferably 3.
  • the CONR 5 moiety is preferably in an equatorial orientation to the bicyclic system.
  • the invention also provides compounds within formula (I) of formula (II) and pharmaceutically acceptable salts and solvate and N-oxides thereof: wherein:
  • the benzamide moiety in the compound of formula (II) is of formula (III): wherein:
  • R 2 2 is C 1-6 alkoxy
  • R 3 2 is hydrogen
  • R 4 2 is C 1-6 alkylthio
  • a particularly preferred moiety of formula (IV) is wherein R 1 2 is methoxy, R 2 2 is methoxy, R 3 2 is hydrogen and R 4 2 is methylthio.
  • R 6 , p and q are as described under formula (I).
  • q is 1 and the moiety of formula (III) is then attached at the 3-position numbering through the -(CH 2 )q containing ring from a bridgehead atom taken as 1 (not necessarily standard numbering).
  • R 1 2 , R 2 2 , R 3 2 and R4 2 are as described under formula (III).
  • a sub-group of compounds within formula (IV) is of formula (V): wherein:
  • R 1 2 , R 2 2 , R 3 2 , R 4 2 and R 6 are as hereinbefore described in relation to formula (III).
  • R 6 is unsubstituted benzyl.
  • CONH moiety is in the ⁇ -orientation to the nortropane ring, that is as follows:
  • a preferred sub-group of compounds within formula (IV) is of formula (VI):
  • R 1 2 , R 2 2 , R 3 2 , R 4 2 and R 6 are as described under formulae (I) and (III).
  • R 6 is preferably benzyl optionally 4-substituted by fluoro, chloro or methyl.
  • CONH moiety is in the ⁇ -orientation to the granatane ring, the ⁇ -orientation being the same as in the nortropane hereinbefore depicted.
  • R 6 is C l-7 alkyl, such as C 5-7 alkyl, 2-thienylmethyl or -(CH 2 ) t R 8 as defined in formula (I).
  • the invention also provides compounds within formula (I) of formula (VII): wherein:
  • Suitable values for R 1 3 , R 3 3 , R 4 3 and R 6 include those described in relation to formula (I) for R 1 , R 3 , R 4 and R 6 respectively.
  • R1 3 is preferably methoxy.
  • R 3 1 is preferably amino or C 1-4 alkanoylamino, most preferably amino.
  • R 4 3 is preferably methylthio.
  • a particularly preferred benzamide moiety is formula (VII), therefore is wherein R 1 3 is methoxy, R 3 3 is amino and R 4 3 is methylthio.
  • R 1 3 , R 3 3 , and R 6 are as hereinbefore described in relation to formula (VII).
  • R 6 is preferably benzyl.
  • CONH moiety is in the ⁇ -orientation to the nortropane ring as hereinbefore depicted.
  • a preferred sub-group of compounds within formula (VII) is of formula (IX): wherein R 1 3 , R33, R 4 3 and R 6 are as hereinbefore defined.
  • R 1 3 , R 3 3 and R 4 3 are as hereinbefore described in relation to formula (VII).
  • R 6 is preferably benzyl optionally substituted by fluoro, chloro or methyl.
  • CONH moiety is in the ⁇ -orientation to the granatane ring, the ⁇ -orientation being the same as in the nortropane hereinbefore depicted.
  • Particularly suitable examples of the compounds of the present invention include those of the Examples hereinafter.
  • the compounds of the formula (I) and in particular compounds of formulae (II) and (VII) have chiral or prochiral centres, and thus are capable of existing in a number of stereoisomeric forms.
  • the invention extends to each of the stereoisomeric forms of compounds of formulae (II) and VII) and to compositions containing each of the stereoisomeric forms of compounds of formula (I) and a pharmaceutically acceptable carrier.
  • the leaving group Q is a group that is readily displaceable by a nucleophile.
  • examples of such groups are hydroxy, halogen such as chloro and bromo and acyloxy such as Cl-4 alkanoyloxy C 1-4 alkoxycarbonyloxy and activated hydrocarbyloxy such as pentachlorophenoxy.
  • a leaving group is hydroxy
  • the reaction is preferably carried out in an inert non-hydroxylic solvent, such as benzene, toluene or diethyl ether in the presence of a dehydrating catalyst, such as a carbodiimide, for example dicyclohexylcarbodiimide.
  • a dehydrating catalyst such as a carbodiimide, for example dicyclohexylcarbodiimide.
  • the reaction may be carried out at a non-extreme temperature such as -10 to 100°C, for example 0 to 80°C.
  • a leaving group is a halide
  • the reaction is preferably carried out at a non-extreme temperature in an inert non-hydroxylic solvent, such as benzene, toluene or diethyl ether. It is also preferably carried out in the presence of an acid acceptor, such as an organic base, in particular a tertiary amine, such as triethylamine, trimethylamine, pyridine or picoline, some of which can also function as the solvent.
  • the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate.
  • acyloxy If a leaving group is acyloxy, then the reaction is preferably carried in substantially the same manner as if the leaving group were hydroxy.
  • Suitable examples of acyloxy leaving groups include C 1-4 alkanoyloxy, mesyloxy, tosyloxy and triflate.
  • a leaving group is C 1-4 alkoxycarbonyloxy
  • the reaction is preferably carried out in an inert solvent, such as methylenechloride,at a non-extreme temperature in the presence of an acid acceptor, such as triethylamine.
  • a leaving group is activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as dimethylformamide. It is also preferred that the activated hydrocarbyloxy group is a pentachlorophenyl ester and that the reaction is carried out at ambient temperature.
  • Q is halogen, such as chloro.
  • the compounds of formula (X) and (Xl) are either known compounds or can be prepared analogously to the preparation of structurally similar known compounds.
  • Compounds of formula (X) wherein R l and R 2 together form ethylenedioxy may be formed by heating a compound of formula (X) wherein R 2 is hydroxy and R 1 is replaced by an hydroxy group with dibromoethane in the presence of an inorganic base such as potassium hydroxide or potassium carbonate using ethanol-water as solvent.
  • an inorganic base such as potassium hydroxide or potassium carbonate
  • Compounds of formula (X) wherein the third of R 2 , R 3 and R 4 is aminosulphonyl may be formed from the corresponding chlorosulphonyl derivatives of the compound of formula (X) wherein R 2 , R3 or R 4 is replaced by hydrogen, with a suitable amine and ammonia.
  • the reduction is carried out with a reagent suitable for reducing nitroanisole to aminoanisole
  • deacylation is carried out by treatment- with a base, such as an alkali metal hydroxide.
  • the acylation is carried out with an acylating agent, such as the corresponding acid or acid chloride.
  • Formylation is carried out with the free acid.
  • halogenation is carried out with conventional halogenating agents.
  • oxidation is carried out at below ambient temperatures in a non-aqueous solvent, such as a chlorinated hydrocarbon, in the presence of an organic peracid, such as 3-chloroperbenzoic acid, or in water in the presence of a soluble strong inorganic oxidant, such as an alkali metal permananate or in aqueous hydrogen peroxide.
  • a non-aqueous solvent such as a chlorinated hydrocarbon
  • an organic peracid such as 3-chloroperbenzoic acid
  • a soluble strong inorganic oxidant such as an alkali metal permananate or in aqueous hydrogen peroxide.
  • R. 6 which is optionally substituted benzyl as hereinbefore defined, may be replaced by another group R 6 .
  • R 6 benzyl groups may be removed for example when R 2 , R 3 or R 4 is not halogen by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (XII) : wherein the variable groups are as defined in formula (I).
  • An optional process step in the preparation of a compound of the formula (I) therefore comprises the reaction of a corresponding compound of the formula (XII) as hereinbefore defined with a compound Q 2 R 6 wherein R 6 is as defined in formula (I) and Q 2 is a leaving group, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I).
  • Suitable value for Q 2 include groups readily displaced by nucleophiles such as Cl, Br, I, OSO 2 CH 3 or OSO 2 C 6 H 4 pCH 3 .
  • Favoured values for Q 2 include Cl, Br and I.
  • the compound Q 3 R 6 is a benzyl halide such as the bromide or chloride.
  • the reaction may be carried out under conventional alkylation conditions for example in an inert solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate.
  • an acid acceptor such as potassium carbonate.
  • the reaction is carried out at non-extreme temperature such as at ambient or at a slightly elevated temperature.
  • the -CO-NR 5 - linkeage may have an a or ⁇ orientation with respect to the ring of the bicyclic moiety to which it is attached.
  • a mixture of a and a isomers of the compound of the formula (I) may be synthesised non- stereospecifically and the desired isomer separated conventionally therefrom e.g. by chromatography; or alternatively the a and a isomer may if desired be synthesised from the corresponding a or ⁇ form of the compound of the formula (XI).
  • the a or ⁇ form of the compound of the formula (XI) may if desired be prepared by known stereospecific processes, such as those leading to the a or ⁇ isomers of the compound of the formula (XI) depicted in the Scheme and described in the Descriptions hereinafter.
  • the invention provides a process for the preparation of a compound of formula (II) which.process comprises reacting a compound of formula (XIII): with a compound of formula (XIV) wherein the variable groups are as hereinbefore defined; and thereafter converting a group , or in the thus formed compound to another group , , respectively; converting R 6 to (other) R 6 ; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).
  • the invention further provides an optional process for the preparation of a compound of formula (II) which comprises the reaction of a compound of formula (XV): with Q 2 R 6 as hereinbefore defined.
  • the invention further provides a process for the preparation of a compound of formula (VII) which process comprises reacting a compound of formula (XVI): with a compound of formula (XVI): wherein R is R or a nitro group; the variable groups are as hereinbefore defined; and thereafter if necessary converting a group R , R or R in the thus formed compound to another R , R or another R group respectively; converting R 6 to (other) R 6 , and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).
  • the invention further provides an optional process for the preparation of a compound of formula (VII) which process comprises the reaction of a compound of formula (XVIII): with Q 2 R 6 as hereinbefore defined.
  • Methyl-4-amino-2-methoxy benzoate (14.0g, 0.0774 mole) was dissolved in methanol (400ml) containing potassium thiocyanate (15.0g). Bromine (4.25ml) in methanol (20ml) was added dropwise with stirring at room temperature over lhr. The solution was stirred for a further hour then poured into water (1L). The precipitate was filtered and washed with water and dried in vacuo to yield the title compound (14.58g;79%) mp 184-185° (i.r. SCN 2150 cm -1 (s)).
  • Methyl-4-amino-2-methoxy-5-thiocyanobenzoate (50.18g, 0.211 mole) was dissolved in methanol (1.5L) containing potassium hydroxide (70g). The solution was warmed to 60° for 1 hour then methyl iodide (20ml) was added dropwise aver 2 hours. The mixture was heated to reflux for 1 hour and then evaporated to 1/4 volume. Inorganic salts were filtered and the filtrate evaporated in vacuo to dryness. The solid was dissolved in water (200ml) and filtered (1.2g-methyl ester of title compound). Acidification of the filtrate gave the title compound which was filtered, washed with water and dried in vacuo. (33.Og; 73%) np 152-154°.
  • 2,3-Dimethaxybenzoic acid (5g) was added in small portions to chlorosulphonic acid (10mls) keeping the temperature of the mixture below 5°C. The reaction mixture was then warmed to 55°C and maintained at this temperature for 2 hours before cooling and pouring into ice-water.
  • Tin (11) chloride 26g was added in portions to a suspension of 5-chlorosulphonyl-2,3-dimethoxy-benzoic acid (5.5g) in a mixture of concentrated hydrochloric acid (13mls) and water (5mls) and the mixture was stirred for 4 hours.
  • the disulphide (D5) (4.0g) was heated under reflux in 10% sodium hydroxide solution (100ml) for 1 hour, before filtration of the hot solution. The filtrate was allowed to cool before the addition of dimethyl sulphate (3mls). After standing at roan temperature overnight the solution was acidified with 5N hydrochloric acid, filtered and dried over potassium hydroxide in vacuo to give 2,3-dimethoxy-5-methylthiobenzoic acid (1.2g, 28%) m.pt. 139-141°C.
  • 2,3-Dimethoxy-5-methylthiobenzoic acid (1.13g) was suspended in dry dichloromethane (30ml) with oxalyl chloride (0.44ml) and dry dimethylformamide (0.5ml) added. The mixture was stirred at roan temperature until it became homogeneous.
  • the reaction mixture was allowed to warm to room temperature before being shaken with 10% sodium hydroxide solution (10ml).
  • the test is based on that described by Protais, P., Constantin, J. and Schwartz J.C. (1976), Psychopharmacology, 50, 1-6.
  • mice When mice are given a dose of 1 mg/kg apomorphine and then placed in an enclosed environment, such as an inverted wire cage, they are seen to climb around the walls. This behavioural phenomenon is thought to be a consequence of the stimulation of post-synaptic Dopamine (D.A.) receptors in the nucleus accunbens. Inhibition of apomorphine induced climbing is therefore indicative of post-synaptic D.A. receptor blockade in the aocumbens.
  • D.A. post-synaptic Dopamine
  • mice Groups of 10 male CD1 mice, weighing 25-30g were pre-treated orally with either graded doses of the test compound or vehicle, at appropriate time intervals before the subcutaneous administration of a sub-maximal dose of apomorphine (1 mg/kg). Immediately after the apomorphine injection the mice were placed in wire climbing cages' and each animal was scored for climbing behaviour at 10 and 20 minutes post apomorphine as follows:-
  • test compound was administered subcutaneously 30 minutes prior to administration of apomorphine.
  • the total score was calculated for each group of mice and expressed as a percentage inhibition of climbing.
  • ED50's and fiducial limits were calculated according to the method of Litchfield and Wilcoxon, the ED50 being the dose that produced a 50% inhibition of apomorphine - induced climbing.
  • the table shows the results cbtained.

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EP82302829A 1981-06-17 1982-06-02 Alkylthioderivate von Azabicyclobenzamiden, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen Expired EP0067615B1 (de)

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GB8118603 1981-06-17
GB8118603 1981-06-17
GB8118604 1981-06-17
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GB8119998 1981-06-29
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EP0093488A2 (de) * 1982-03-18 1983-11-09 Beecham Group Plc Nortropyl-Benzopyrrolinon-Verbindungen, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
EP0095262A1 (de) * 1982-05-11 1983-11-30 Beecham Group Plc Azabicycloalkanderivate, ihre Herstellung und sie enthaltende Arzneimittel
EP0220011A2 (de) * 1985-10-12 1987-04-29 Beecham Group Plc Verwendung von Azabicycloalkylbenzamiden zur Behandlung von Magen-Darmbewegungskrankheiten, Migräne, Emesis, Migränekopfschmerzen, Trigeminusneuralgie und Arhythmie
EP0227215A1 (de) * 1985-09-19 1987-07-01 Beecham Group Plc 1-Azatricycloalkylbenzamide, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen
US4820715A (en) * 1984-06-28 1989-04-11 Bristol-Myers Company Anti-emetic quinuclidinyl benzamides
US5011992A (en) * 1984-06-28 1991-04-30 Bristol-Myers Squibb Company Pharmacologically active substituted benzamides
US5240957A (en) * 1984-01-31 1993-08-31 Astra Lakemedel Akteibolag Oxysalicylamido derivatives

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FI74707C (fi) * 1982-06-29 1988-03-10 Sandoz Ag Foerfarande foer framstaellning av terapeutiskt anvaendbara alkylenoeverbryggade piperidylestrar eller -amider av bicykliska karboxylsyror.
DE3429830A1 (de) * 1983-08-26 1985-03-07 Sandoz-Patent-GmbH, 7850 Lörrach Automatische carbonsaeure- und sulfonsaeureester oder -amide
DE3445377A1 (de) * 1983-12-23 1985-07-04 Sandoz-Patent-GmbH, 7850 Lörrach Carbocylische und heterocyclische carbonsaeureester und -amide von ueberbrueckten und nicht ueberbrueckten cyclischen stickstoffhaltigen aminen oder alkoholen
EP0201165B1 (de) * 1985-03-14 1994-07-20 Beecham Group Plc Arzneimittel zur Behandlung von Emesis
US4713391A (en) * 1986-04-17 1987-12-15 The United States Of America As Represented By The Secretary Of The Army Azabicyloalkane phenyl substituted alkane carboxylates, their preparation and use as anticholinergic agents
EP0604494B1 (de) * 1991-09-12 1999-07-28 Smithkline Beecham Plc 5-ht4 rezeptor antagonisten
US5314899A (en) * 1992-03-03 1994-05-24 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Epibatidine and derivatives, compositions and methods of treating pain
GB9301660D0 (en) * 1993-01-28 1993-03-17 Smithkline Beecham Plc Pharmaceuticals
US5948933A (en) 1997-07-11 1999-09-07 Organix, Inc. Tropane analogs and methods for inhibition of monoamine transport
US5726189A (en) * 1996-05-03 1998-03-10 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Method for imaging nicotinic acetylcholinergic receptors in the brain using radiolabeled pyridyl-7-azabicyclo 2.2.1!heptanes
JP2001221177A (ja) 2000-02-10 2001-08-17 Sanden Corp スクロール型流体機械
DE20120708U1 (de) 2001-10-09 2002-08-01 Blundell, Paul, Sommerville, Mass. Tropan-Analoga zur Inhibierung des Monoamin-Transports
UA82517C2 (uk) * 2003-06-24 2008-04-25 Ньюросерч А/С Нові похідні 8-аза-біцикло[3.2.1]октану та їх застосування як інгібіторів ресорбції моноамінових медіаторів

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FR2446823A1 (fr) * 1979-01-16 1980-08-14 Delalande Sa Nouveaux derives du nor-tropane, leur procede de preparation et leur application en therapeutique
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0093488A2 (de) * 1982-03-18 1983-11-09 Beecham Group Plc Nortropyl-Benzopyrrolinon-Verbindungen, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
EP0093488A3 (de) * 1982-03-18 1984-05-23 Beecham Group Plc Nortropyl-Benzopyrrolinon-Verbindungen, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
EP0095262A1 (de) * 1982-05-11 1983-11-30 Beecham Group Plc Azabicycloalkanderivate, ihre Herstellung und sie enthaltende Arzneimittel
US5240957A (en) * 1984-01-31 1993-08-31 Astra Lakemedel Akteibolag Oxysalicylamido derivatives
US4820715A (en) * 1984-06-28 1989-04-11 Bristol-Myers Company Anti-emetic quinuclidinyl benzamides
US5011992A (en) * 1984-06-28 1991-04-30 Bristol-Myers Squibb Company Pharmacologically active substituted benzamides
EP0227215A1 (de) * 1985-09-19 1987-07-01 Beecham Group Plc 1-Azatricycloalkylbenzamide, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen
US4816453A (en) * 1985-09-19 1989-03-28 Beecham Group, P.L.C. N-heterocyclic derivatives of benzamides and their use in treating gastric and intestinal disorders
EP0220011A2 (de) * 1985-10-12 1987-04-29 Beecham Group Plc Verwendung von Azabicycloalkylbenzamiden zur Behandlung von Magen-Darmbewegungskrankheiten, Migräne, Emesis, Migränekopfschmerzen, Trigeminusneuralgie und Arhythmie
EP0220011A3 (de) * 1985-10-12 1990-01-03 Beecham Group Plc Verwendung von Azabicycloalkylbenzamiden zur Behandlung von Magen-Darmbewegungskrankheiten, Migräne, Emesis, Migränekopfschmerzen, Trigeminusneuralgie und Arhythmie

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US4499099A (en) 1985-02-12
EP0067615B1 (de) 1986-01-08
AU8493282A (en) 1982-12-23
DE3268378D1 (en) 1986-02-20

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